Regulation of human brown adipose tissue activity

Abstract

The rising prevalence of obesity globally poses significant morbidity and mortality, as obesity increases the risk of developing a number of diseases such as diabetes, hypertension and cardiovascular disease. While some more recent interventions to treat obesity have been efficacious, they can cause undesirable side effects, highlighting a need for novel treatment options. Adipose tissue comprises brown (BAT) and white adipose tissue (WAT). WAT mainly stores energy, while BAT increases energy expenditure primarily through cold-induced thermogenesis, which is mediated through a specialised thermogenic protein, called uncoupling protein 1 (UCP1). Due to its role in thermogenesis, BAT has gained significant interest as a target to treat obesity and associated cardiometabolic disease. 2-deoxy-2- [¹⁸F]fluoro-D-glucose (¹⁸F-FDG) positron emission tomography (PET) is the most commonly used technique to quantify human BAT mass and activity, exploiting the substantial glucose uptake by BAT as a surrogate marker for BAT thermogenesis. The prevalence of detectable BAT at room temperature using ¹⁸F-FDG PET is reduced in individuals with increased cardiovascular risk such as obesity, diabetes and hypertension. However, ¹⁸F-FDG uptake by BAT may be confounded by obesity-induced insulin resistance so it remains unclear whether BAT thermogenesis is decreased in obesity and cardiometabolic disease. Our understanding of the regulation of human BAT activation also remains limited. Using transcriptomics, we recently identified serotonin as a potential regulator of human BAT, by demonstrating that the gene SLC6A4, which encodes the serotonin reuptake transporter (SERT), was one of the most differentially expressed genes in human brown compared with white adipocytes. SERT inhibition, which increases serotonin receptor activation, decreased human brown adipocyte thermogenesis. However, it is unknown whether serotonin levels are altered in obesity or if reduction in peripheral serotonin activity can lead to a therapeutic benefit. We hypothesised that (1) UCP1 expression in human BAT, a marker of BAT thermogenic capacity, is inversely associated with cardiovascular risk factors, (2) circulating and adipose tissue serotonin levels are increased in obesity and (3) inhibition of peripheral serotonin synthesis stimulates human BAT activity. To assess hypothesis 1, we measured UCP1 mRNA expression in whole adipose tissue (n=53) and in differentiated pre-adipocytes (n=85) from paired BAT and WAT biopsy samples obtained from patients undergoing elective neck surgery. UCP1 expression in BAT (but not in WAT or in differentiated brown or white pre-adipocytes) was inversely associated with obesity, ageing, insulin resistance and hypertension. Age was the only independent predictor of high UCP1 expression in BAT and obesity reduced the frequency of high UCP1 expression only in individuals >40 years. To explore the effect of obesity in young adults in vivo, ¹⁸F-FDG PET-MR scans were performed in young obese and age-matched normal weight individuals (n=6 in each weight group, mean age ~22 years) following 2 hours of mild cold exposure. Consistent with the UCP1 data, young individuals with obesity had preserved ¹⁸F-FDG uptake by BAT, despite increased insulin resistance. To determine if obesity alters peripheral serotonin levels, we measured circulating and abdominal adipose tissue serotonin concentrations in healthy age-matched individuals with normal body weight and obesity (n=10 in each weight group) during warm and cold exposure. The majority of circulating serotonin is inactive due to being platelet-bound with only a small proportion circulating freely. Platelet serotonin concentrations increased during cold exposure in normal weight individuals. However, in obese volunteers, inactive platelet serotonin levels increased during warm conditions, which dropped during cold exposure, accompanied by an increase in adipose tissue serotonin levels. These variations in serotonin concentrations suggest a potential dysregulation in cold-induced serotonin response in obesity. To assess whether inhibition of peripheral serotonin synthesis altered BAT activity, we undertook a double-blind crossover study in 8 healthy normal weight subjects and 8 participants with obesity. These volunteers were given placebo and telotristat ethyl tablets (an inhibitor of peripheral serotonin synthesis) for 2 weeks in random order. Telotristat ethyl reduced ¹⁸F-FDG uptake by BAT, increased total cholesterol levels and suppressed the rise in noradrenaline and insulin levels following cold exposure and oral glucose load respectively. In conclusion, UCP1 expression in BAT is reduced with ageing, obesity and cardiometabolic disease, in keeping with BAT dysfunctio